A simple bias correction in linear regression for quantitative trait association under two-tail extreme selection

Selective genotyping can increase power in quantitative trait association. One example of selective genotyping is two-tail extreme selection, but simple linear regression analysis gives a biased genetic effect estimate. Here, we present a simple correction for the bias. © The Author(s) 2011.published_or_final_versionSpringer Open Choice, 21 Feb 201

Replication study of genetic loci influencing age at menopause in Southern Chinese women

Session - Ovarian AgeingThis journal issue contain Abstracts: 10th EMAS Congress 2015INTRODUCTION: Age at menopause is a highly heritable trait. Previous genome-wide meta-analysis in European and Northern Chinese identified 26 loci underlying age at menopause. OBJECTIVES: To validate these 26 genetic loci in Southern Chinese women. AIMS: To study genetic factors which may influence age at menopause in Southern Chinese. METHODS: This study was performed on 653 women who participated in the Hong Kong Osteoporosis Study, whose age at menopause was available. These women consented to have blood taken and archived for genotyping. DNA was extracted from the buffy coat, and genotyping was performed using Sequenom iPLEX. Age at menopause ...postprin

PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion

Background: Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation. Methods: As PMCA4 removes cytosolic calcium, we measured transient changes and the time-dependent decay of cytosolic calcium level as visualized by using fura-2 fluorescent dye with confocal microscopy in human SH-SY5Y neuroblastoma cells overexpressing either wild-type or R268Q mutant PMCA4. Results: Overexpressing both wild-type and R268Q PMCA4 significantly reduced maximum calcium surge after KCl-induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA4 protein demonstrated significantly higher level of calcium surge when compared with wild-type. Furthermore, the steady-state cytosolic calcium concentration in these mutant cells remained markedly higher than the wild-type after SERCA inhibition by thapsigargin. Conclusion: Our result showed that p.R268Q mutation in PMCA4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP. © 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.published_or_final_versio

PMCA4 (ATP2B4) Mutation in Familial Spastic Paraplegia

Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. In this study, we identified a novel missense mutation (c.803G.A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP using whole-exome sequencing and confirmed with Sanger sequencing. This mutation co-segregated with the phenotype in the six family members studied and is predicted to be pathogenic when multiple deleteriousness predictions were combined. This novel R268Q mutation was not present in over 7,000 subjects in public databases, and over 1,000 Han Chinese in our database. Prediction of potential functional consequence of R268Q mutation on PMCA4 by computational modeling revealed that this mutation is located in protein aggregation-prone segment susceptible to protein misfolding. Analysis for thermodynamic protein stability indicated that this mutation destabilizes the PMCA4 protein structure with higher folding free energy. As PMCA4 functions to maintain neuronal calcium homeostasis, our result showed that calcium dysregulation may be associated with the pathogenesis of FSP.published_or_final_versio

Investigating poultry trade patterns to guide avian influenza surveillance and control: a case study in Vietnam

Live bird markets are often the focus of surveillance activities monitoring avian influenza viruses (AIV) circulating in poultry. However, in order to ensure a high sensitivity of virus detection and effectiveness of management actions, poultry management practices features influencing AIV dynamics need to be accounted for in the design of surveillance programmes. In order to address this knowledge gap, a cross-sectional survey was conducted through interviews with 791 traders in 18 Vietnamese live bird markets. Markets greatly differed according to the sources from which poultry was obtained, and their connections to other markets through the movements of their traders. These features, which could be informed based on indicators that are easy to measure, suggest that markets could be used as sentinels for monitoring virus strains circulating in specific segments of the poultry production sector. AIV spread within markets was modelled. Due to the high turn-over of poultry, viral amplification was likely to be minimal in most of the largest markets. However, due to the large number of birds being introduced each day, and challenges related to cleaning and disinfection, environmental accumulation of viruses at markets may take place, posing a threat to the poultry production sector and to public health

Clinical management guidelines for osteoporosis in Hong Kong

The following guidelines provide a basis for the management of osteoporosis for the practising physician in Hong Kong. The guidelines have been complied by a working group that represents the specialties concerned with osteoporosis and summarise the current management of osteoporosis based on available published evidence and relevant local experience.published_or_final_versio

European bone mineral density loci are also associated with BMD in East-Asian populations

Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10 -9), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10 -5), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10 -5), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10 -5), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians. © 2010 Styrkarsdottir et al.published_or_final_versio

Genome-wide Haplotype Association Mapping in mice identifies a genetic variant in CER1 associated with bone mineral density and fracture in southern Chinese women

INTRODUCTION: Osteoporosis is characterized by a decrease in bone mass, deterioration of bone tissue, impaired bone strength and increased fracture risk. It is a medically, socially, and economically important disease, especially among the aging population. Bone Mass Density (BMD) is a quantitative index of osteoporosis. Acquisition of bone mineral is a complex process involving genetics and environmental factors. METHODS: A genome-wide Haplotype Association Mapping (HAM) approach was performed by using inbred mice strains which had been genotyped and phenotyped in the Mouse Phenome Project. In HAM, a dense SNPs map was first partitioned into blocks of three SNPs with an average length of 1Mb. Modified F-statistics were calculated for the whole genome to test if blocks exist where the haplotypes can partition inbred strains into high and low BMD groups. In this study, the candidate gene Cerberus 1 (Cer1) suggested from HAM analysis was eventually tested by a human case-control cohort of 1,083 subjects. RESULTS AND CONCLUSION: In this study, we used a HAM approach to identify a haplotype block within Cer1 that partitions inbred mice strains into high and low BMD groups. A cohort of 1083 high and low BMD human subjects were studied and a non-synonymous SNP (rs3747532) in human CER1 was identified to be associated with increased risk of both low BMD in premenopausal women (OR 2.2; 95% confidence interval: 1.0 - 4.6; p < 0.05) and increased risk of vertebral fractures (OR 1.82, p=0.025) in the post-menopausal cohort. We also showed that Cer1 is expressed in mouse bone and growth plate by RT-PCR, immunohistochemistry and in situ hybridization, consistent with polymorphisms potentially influencing bone mineral density. Our successful identification of an association with CER1 in humans together with our mouse study suggests that CER1 may play a role in the development of bone or its metabolism.postprintThe 59th Annual Meeting of The American Society of Human Genetics (ASHG), Honolulu, HI., 20-24 October 2009

Burden of rare variants in ALS genes influences survival in familial and sporadic ALS

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Identification of an N-terminal 27 kDa fragment of Mycoplasma pneumoniae P116 protein as specific immunogen in M. pneumoniae infections

<p>Abstract</p> <p>Background</p> <p><it>Mycoplasma pneumoniae </it>is an important cause of respiratory tract infection and is increasingly being associated with other diseases such as asthma and extra-pulmonary complications. Considerable cross-reactivity is known to exist between the whole cell antigens used in the commercial serological testing assays. Identification of specific antigens is important to eliminate the risk of cross-reactions among different related organisms. Adherence of <it>M. pneumoniae </it>to human epithelial cells is mediated through a well defined apical organelle to which a number of proteins such as P1, P30, P116 and HMW1-3 have been localized, and are being investigated for adhesion, gliding and immunodiagnostic purposes.</p> <p>Methods</p> <p>A 609 bp fragment P116_(N-27),corresponding to the N-terminal region of <it>M. pneumoniae </it>P116 gene was cloned and expressed. A C-terminal fragment P1_(C-40),of P1 protein of <it>M. pneumoniae </it>was also expressed. Three IgM ELISA assays based on P116_(N-27),P1_(C-40)and (P116 _(N-27)+ P1_(C-40)) proteins were optimized and a detailed analysis comparing the reactivity of these proteins with a commercial kit was carried out. Comparative statistical analysis of these assays was performed with the SPSS version 15.0.</p> <p>Results</p> <p>The expressed P116_(N-27)protein was well recognized by the patient sera and was immunogenic in rabbit. P1_(C-40)of <it>M. pneumoniae </it>was also immunogenic in rabbit. In comparison to the reference kit, which is reported to be 100% sensitive and 75% specific, ELISA assay based on purified P116_(N-27),P1_(C-40)and (P116_(N-27)+ P1_(C-40)) proteins showed 90.3%, 87.1% and 96.8% sensitivity and 87.0%, 87.1% and 90.3% specificity respectively. The p value for all the three assays was found to be < 0.001, and there was a good correlation and association between them.</p> <p>Conclusion</p> <p>This study shows that an N-terminal fragment of P116 protein holds a promise for serodiagnosis of <it>M. pneumoniae </it>infection. The IgM ELISA assays based on the recombinant proteins seem to be suitable for the use in serodiagnosis of acute <it>M. pneumoniae </it>infections. The use of short recombinant fragments of P116 and P1 proteins as specific antigens may eliminate the risk of cross-reactions and help to develop a specific and sensitive immunodiagnostic assay for <it>M. pneumoniae </it>detection.</p